tbuckley/cabot-search huggingface dataset:
Abstract PO-077: High-throughput 3D-spheroid invasion assay: A powerful tool to identify novel drugs targeting tumor micro-environment in HNSCC
Authors: Kunal Karve, Stephanie Poon, Panagiotis Prinos, Laurie Ailles
Journal: Clinical Cancer Research (2023)

Abstract Cancer metastasis is a complex cascade that involves activation of cancer cell invasion and migration. This activation is greatly attributed by multiple factors, including the tumor-microenvironment (TME). Cancer-associated fibroblasts (CAF), a prominent cell type within the TME, have been shown to promote cancer cell invasion and migration, causing metastasis in various cancers including head and neck squamous cell carcinoma (HNSCC). The molecular mechanisms of how CAFs promote HNSCC invasion remain elusive. Our research goal is to understand how CAFs influence HNSCC cells to become invasive and potentially metastatic. Using a top-down research approach, our aim is to identify novel therapeutic chemical probe/drug regimens that potentially target CAF-dependent HNSCC cancer cell-invasion. In-order to perform high-throughput small molecule screens, we have established a 384-well format, three-dimensional (3D) spheroid invasion assay, as a powerful tool to study CAF-dependent HNSCC cancer cell invasion. This platform is currently being used to screen small molecule libraries and identify putative molecular targets, providing insights into underlying mechanisms of CAF-induced cancer cell invasion and candidate therapeutic strategies. Citation Format: Kunal Karve, Stephanie Poon, Panagiotis Prinos, Laurie Ailles. High-throughput 3D-spheroid invasion assay: A powerful tool to identify novel drugs targeting tumor micro-environment in HNSCC [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-077.
Abstract PO-087: Single-cell transcriptome analysis reveals functional changes in tumor-infiltrating macrophages after nutraceutical momordicine-I treatment in head &amp; neck cancer
Authors: Subhayan Sur, Robert Steele, Ratna B. Ray
Journal: Clinical Cancer Research (2023)

Abstract Head &amp; neck cancer is the sixth most prevalent cancer in the world, and oral cancer is the most common subtype with limited effective treatment options. Therefore, there is a critical need to understand the pathogenesis and therapeutic modalities for successful management of head &amp; neck cancer. Momordicine-I (M-I), an active component of bitter melon extract, displayed anti-tumor activity. However, M-I mediated immune modulation of head &amp; neck tumor microenvironment (TME) remains unknown. To improve the efficacy of therapy, it is important to understand the heterogeneity of head &amp; neck cancer in TME and its modulation following treatment at molecular level. In this study, we showed that M-I inhibits head &amp; neck tumor growth in an immunocompetent mouse model. To understand the in-depth changes in immune system, we analyzed the transcriptome profiles of vehicle treated and M-I-treated tumors using single-cell RNA-sequencing. M-I treatment modulates several molecules in monocyte/macrophage clusters in CD45+ populations. Tumor-associated macrophages (TAMs) are crucial barriers to their antitumor effects. We observed that the expression of Sfln4, a myeloid cell differentiation factor, and Cxcl3, a neutrophil chemoattractant, in the monocyte/macrophage populations was significantly reduced following M-I treatment. We further showed that macrophages need to be in close contact with tumor cells to reduce Sfln4 or Cxcl3 expression, suggesting that TAMs are modulated by M-I treatment. Co-culture of macrophages and tumor cells enhances Nos2 expression following M-I treatment, implicating an alteration of the M2 to M1 phenotype of macrophages. In fact, differential expression of macrophage populations from M-I treated tumors showed downregulation of several M2 macrophage marker genes, and their further validations for functional consequence are underway. Together, our results highlight a potential mechanism of immune modulation by M-I, which may help in the development of a combination therapy for head &amp; neck cancer. Citation Format: Subhayan Sur, Robert Steele, Ratna B. Ray. Single-cell transcriptome analysis reveals functional changes in tumor-infiltrating macrophages after nutraceutical momordicine-I treatment in head &amp; neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-087.
Abstract PO-047: A novel saliva miRNA panel of promising diagnostic biomarkers for oral cancer: The association of miR-21 with smoking history
Authors: Dimitra Vageli, Panagiotis G. Doukas, Benjamin L. Judson
Journal: Clinical Cancer Research (2023)

Abstract Introduction: Tobacco use is implicated in the carcinogenesis of oral squamous cell carcinoma (OSCC), which is associated with poor survival if not diagnosed early. It is urgent to develop a novel non-invasive and highly sensitive risk assessment and diagnostic method to screen OSCC. Here, we explored salivary miRNAs as a screening method for OSCC in a high-risk group of patients, such as smokers. Materials and methods: Saliva was collected from 44 individuals (23 HPV-negative OSCC; 21 controls; an equal number of smokers and non-smokers). Twenty head and neck cancer-related miRNA markers were analyzed by qPCR, using dual-labeled probes (miR-20A, miR-21, miR-27B, miR-29A, miR-29B, miR-29C, miR-31, miR-34a, miR-99a, miR-125a, miR-136, miR-139, miR-155, miR-192, miR-200A, miR-375, miR-425A, miR-451a, miR-504, miR-3928; RNU6 control), and by Welch’s t-test and ROC (receiver operating characteristic) curve; GraphPad Prism 7.0. Results: A panel of 4 miRNA markers (miR-21, miR-136, miR-3928, miR-29B) was found to be significantly overexpressed in the saliva of OSCC versus healthy controls with a diagnostic ability (p&amp;lt;0.05 by Welch’s t-test; AUC (area under the ROC curve): 64-85%, sensitivity: 50-67%, specificity: 32-38%; 95% confidence interval; by ROC curve analysis). “Oncomir” miR-21 levels (miR-21/RNU6) were found to be significantly higher in the saliva of OSCC patients with a smoking history (mean ± SD: 0.17 ± 0.19) versus never-smokers (mean ± SD: 0.0056 ± 0.0075) (p&amp;lt;0.05; by t-test) with a diagnostic ability (AUC: 90%, sensitivity: 68%, specificity: 30%; 95% confidence interval). Conclusions: We provide a novel panel of non-invasive, easy-to-apply, and sensitive biomarkers, for the diagnosis of oral cancer, including miR-21 in individuals with a smoking history, encouraging their validation in a large group of head and neck cancer patients. Citation Format: Dimitra Vageli, Panagiotis G. Doukas, Benjamin L. Judson. A novel saliva miRNA panel of promising diagnostic biomarkers for oral cancer: The association of miR-21 with smoking history [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-047.
Abstract PO-018: Pathological analysis of newly established immunocompetent mice with full HPV16 genome integration
Authors: Xue Li, Aditi Kothari, Hina Rehmani, Wendell G. Yarbrough, Natalia Issaeva
Journal: Clinical Cancer Research (2023)

Abstract Human papillomaviruses (HPV) are associated with both benign and malignant epithelial lesions. High-risk HPV subtype HPV 16 is the causative agent of cervical and the majority of oropharyngeal squamous cell carcinomas. Despite the continuous increase in the disease burden, mechanisms and pathways of HPV16-induced cancer growth are not fully understood, thus leading to suboptimal treatment. In the last few decades, several transgenic mouse models were developed, which helped tremendously in the study of HPV-induced carcinogenesis. However, all existent HPV transgenic mice were targeted early genes expression driven by an artificial promoter and did not encompass the functionality of the whole HPV genome, including the upstream regulatory region (URR) that contains HPV promoters, regulatory elements, and a replication origin, limited our ability to investigate HPV-associated malignant transformation and the role of host factors in this process. Therefore, we generated HPV16 transgenic mice by using CRISPR/Cas9-mediated genome editing to insert the full-length HPV16 genome into the Rosa26 locus. Two founder mice, with single HPV copy and with tandem HPV integration, were used to establish mouse colonies. Interestingly, regardless of HPV copy number, approximately 50% of the HPV knock-in mice exhibited early death during the first 2 weeks after birth, while surviving pups were significantly smaller than the same-age wild-type mice and had severe hair loss. Intriguingly, the growth retardant and hair loss phenotype in the HPV16 knock-in mice disappeared in approximately 4 weeks, most likely indicating that viral genes compromise specific stages of mouse development. We evaluated the expression of HPV genes during development, in different mouse organs, and in established fibroblasts and epithelial cell cultures. Our newly established HPV16 knock-in mouse model provides viral gene expression from natural viral promoters offering an essential basis to explore the role of cellular factors in HPV-driven pathologies. Citation Format: Xue Li, Aditi Kothari, Hina Rehmani, Wendell G. Yarbrough, Natalia Issaeva. Pathological analysis of newly established immunocompetent mice with full HPV16 genome integration [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-018.
Abstract PO-023: The AP-1 transcription factor component, JunB, regulates the expression of HPV genes in head and neck cancer
Authors: Hina Rehmani, Natalia Isaeva, Travis P. Schrank, Wendell G. Yarbrough
Journal: Clinical Cancer Research (2023)

Abstract Within head and neck squamous cell carcinoma (HNSCC), those induced by the human papillomavirus (HPV+) have a more hypermethylated genome compared to those that are negative (HPV-). Therefore, our lab explored the usage of the demethylating agent 5-azacytidine (5-aza), an FDA-approved drug for the treatment of myelodysplasia and acute myeloid leukemia. Repurposing FDA-approved drugs is a strategic way to quickly provide patients with secondary therapeutic options, especially since the incidence of HPV+ HNSCC is now considered an epidemic in the US and Western Europe. Additionally, initial therapy for patients is aggressive leading to adverse, lifelong side effects. Despite having a higher cure rate than HPV-HNSCC, the recurrence rate is still approximately 30% for HPV+ HNSCC. Our lab has found that HPV+ HNSCC cells are more sensitive than HPV- cells to 5-aza as low doses of 5-aza delayed HPV+ xenograft tumor growth and 5-aza-treated HPV+ tumor samples from patients treated in a window trial had increased cell death. Despite demethylation inducing an active, open chromatin conformation, we also observed a marked downregulation of HPV genes expression after 5-aza. Decreased HPV E6 expression, followed by reactivation of tumor suppressor p53, induced p53-dependent apoptosis in HPV+ HNSCC. This decreased expression of HPV genes is an essential component of 5-aza-associated toxicity toward HPV+ HNSCC. Our lab has recently explored the molecular mechanisms of 5-aza on HPV+ HNSCC. We found that 5-aza transcriptionally downregulated the expression of HPV genes, including oncogenes E6 and E7. Microarray studies show marked downregulation of the proto-oncogene JunB, a component of the transcription factor AP-1 (Activator Protein 1) after 5-aza treatment. Experimental deletion of JunB inhibited oncogenes E6 and E7 and restored p53 but also indicated that untreated HPV+ HNSCCs depend on JunB for clonogenic growth. Through this study, we have identified a novel dependency on JunB in HPV+ HNSCC and revealed a new rational target that is desperately needed to treat recurrent/metastatic patients and decrease the toxicity associated with current treatment. Citation Format: Hina Rehmani, Natalia Isaeva, Travis P. Schrank, Wendell G. Yarbrough. The AP-1 transcription factor component, JunB, regulates the expression of HPV genes in head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-023.
Abstract PO-027: Clinical and genetic associations of biological sex and survival in head and neck squamous cell carcinoma
Authors: Alexandria Yao, Andrew Petti, Nadia Mezghani, Fatemeh Momen-Heravi, Alison M. Taylor
Journal: Clinical Cancer Research (2023)

Abstract Approximately half of all head and neck squamous cell carcinoma (HNSCC) patients die within the five years of diagnosis despite treatment. Some studies have found that women with HNSCC have worse overall prognosis. To investigate the characteristics of HNSCC stratified by biological sex, we analyzed HNSCC samples within the Cancer Genome Atlas dataset from 382 male and 141 female patients. Here, tumors from female patients were more likely to be HPV negative and located in the oral cavity, along with a higher diagnosis age for this patient population. In the tumors of female patients, we also observed increased expression of genes belonged to immune pathways and higher overall immune infiltrate. Although immune infiltrate influences patient prognosis, it did not explain the biological sex disparity in our multivariable Cox proportional hazard model. Instead, across HNSCC, we found that survival differences attributed to biological sex were largely due to differences in diagnosis age and HPV status. However, this was not the case when solely looking at patients with HNSCC in the larynx. In laryngeal HNSCC, women have significantly worse outcome that cannot be attributed to HPV status or other clinical features. Of note, the association of biological sex with outcome in laryngeal HNSCC is also observed in other datasets. The molecular underpinnings of this disparity have not yet been identified, but preliminary analyses suggest different patterns of genomic alterations correlating with biological sex. Our study provides insight into factors that contribute to worse prognosis for females with HNSCC, particularly of the larynx. Citation Format: Alexandria Yao, Andrew Petti, Nadia Mezghani, Fatemeh Momen-Heravi, Alison M. Taylor. Clinical and genetic associations of biological sex and survival in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-027.
Abstract PO-007: A phase 2 open-label study of conditionally active biologic, ozuriftamab vedotin (BA3021) in PD-1/L1 failure patients with recurrent or metastatic squamous cell carcinoma of the head and neck
Authors: Alan L. Ho, Douglas R. Adkins, Jochen Lorch, Jacob S. Thomas, Jaspreet S. Grewal
Journal: Clinical Cancer Research (2023)

Abstract Background: Ozuriftamab vedotin (BA3021) is a conditionally active biologic (CAB) anti-receptor tyrosine kinase orphan receptor 2 (ROR2) humanized monoclonal antibody (IgG1) conjugated to monomethyl auristatin E (MMAE) using a cleavable linker (CAB ROR2 ADC) (Short, et al., 2014, Chang, et al. 2021). Conditional and reversible binding by CABs is designed to reduce off-tumor toxicity and immunogenicity, avoid tissue-mediated drug deposition, and improve pharmacokinetics (PK). ROR2 is a cell-surface transmembrane receptor protein tyrosine kinase highly expressed in several tumor types including head and neck squamous cell cancer (HNSCC). Increased ROR2 expression has been associated with tumor resistance to chemotherapy, programmed death-1 (PD-1) inhibitors, molecular targeted therapy, and radiation therapy. A pronounced unmet need exists as the majority of patients with recurrent or metastatic HNSCC experience disease progression with existing therapies (Chow 2020). Trial Design: BA3021-002 is a multi-center, open-label, single-arm Phase 2 study (n=40) designed to evaluate the efficacy and safety of BA3021 in patients previously treated with PD-(L)1 with ROR-2 expressing recurrent or metastatic HNSCC. Eligible patients include those with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria. Failure to prior treatment is defined as documented disease progression after no more than one PD-1/L1 inhibitor either administered as monotherapy or in combination therapy. Pharmacokinetic (PK), pharmacodynamic (PD), immunogenicity, and biomarker assessments will be performed. Enrollment is ongoing (NCT05271604) References Chang, H.W., Frey, G., Liu, H., Steinman, L., Boyle, W.J. and Short, J.M. Proc. Natl. Acad. Sci. 2021 Mar. 2; 118(9). Chow LQ. Head and neck cancer. N Engl J Med. 2020 Jan 2;382(1):60–72. doi: 10.1056/NEJMra1715715 Short, J.M. Nature Biotechnology 2014 Nov 8, 13(20). Citation Format: Alan L. Ho, Douglas R. Adkins, Jochen Lorch, Jacob S. Thomas, Jaspreet S. Grewal. A phase 2 open-label study of conditionally active biologic, ozuriftamab vedotin (BA3021) in PD-1/L1 failure patients with recurrent or metastatic squamous cell carcinoma of the head and neck [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-007.
Abstract IA09: Characterization of hypoxic tumor microenvironment in HPV-negative HNSCC
Authors: Christine H. Chung
Journal: Clinical Cancer Research (2023)

Abstract Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) which are often associated with heavy tobacco use has one of the most hypoxic tumor microenvironments (TME) among solid tumors. A hypoxic TME is known to be immunosuppressive due to inhibition of T-cell proliferation and effector cytokine production, unfavorable metabolic competition, upregulation of coinhibitory receptors in T-cells, and recruitment of immunosuppressive cells such as myeloid-derived suppressor cells. However, there is no proven therapeutic strategy to remodel the TME to be less hypoxic and proinflammatory. We determined hypoxic HNSCC based on a Hypoxia-Immune gene expression signature, characterized the immune cells in the TME using multiple immunohistochemical staining, and analyzed the signaling pathways to identify potential therapeutic targets. We found that the hypoxic HNSCC had significantly higher numbers of immunosuppressive cells, and patients with hypoxic HNSCC had worse outcomes after treatment with anti-Programmed Cell Death-1 (PD-1) inhibitors such as pembrolizumab and nivolumab. The gene expression analysis showed hypoxic HNSCC predominantly increased the expression of the epidermal growth factor receptor (EGFR) and transforming growth factor-β (TGF-β) pathway genes. Inhibition of EGFR pathway using cetuximab decreased the expression of hypoxia signature genes, suggesting that it may alleviate the effects of hypoxia and remodel the TME to become more proinflammatory. In addition, recent clinical trials evaluating combination of cetuximab and nivolumab as well as combination of BCA101 (an EGFR and TGF-β dual inhibitor) and pembrolizumab showed a significant response in HPV-negative HNSCC. Our study provides a rationale for treatment strategies combining EGFR- and TGF-β-targeted agents and immunotherapy in the management of HPV-negative, hypoxic HNSCC. Citation Format: Christine H. Chung. Characterization of hypoxic tumor microenvironment in HPV-negative HNSCC [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr IA09.
Abstract IA03: Head and Neck Cancer Takes a Nerve, Cancer neuroscience: emerging hallmark of cancer
Authors: Moran Amit
Journal: Clinical Cancer Research (2023)

Abstract Over the past decade, emerging technologies have enabled investigators to begin to bridge the gap between cancer and neuroscience research to unveil the interactive roles of nerves in cancer. We are now beginning to define how the nervous system contributes to cancer initiation, growth, spread, recurrence, and even resistance to oncologic therapeutic strategies. Indeed, neuromodulation with both genetic and pharmacological approaches has been shown to affect not only tumor growth but also antitumor immune response. Collectively, studies have demonstrated a significant and pressing need to recognize cancer neuroscience interplay as a hallmark of cancer to 1) establish the neoneurogenic process as a highly relevant therapeutic target for both the prevention and treatment of cancer, 2) foster interdisciplinary cross-talk among experts in cancer biology and neuroscience, which have traditionally progressed along parallel paths, and 3) integrate human variables such as biological sex, age, race, and gender as underlying factors that can impact cancer neuroscience. Citation Format: Moran Amit. Head and Neck Cancer Takes a Nerve, Cancer neuroscience: emerging hallmark of cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr IA03.
Abstract IA12: Fluorescence guided surgery: Rapidly evolving applications
Authors: Eben L. Rosenthal, Marisa L. Hom, Goulan Lu
Journal: Clinical Cancer Research (2023)

Abstract Despite advances in operative technology, intraoperative methods have not improved cancer detection during surgery in the past 30 years. We propose to test the combination of high-resolution/depth-limited imaging properties of optical imaging agents with the low-resolution/tissue penetrating properties of nuclear agents for detection of primary tumors and regional lymph nodes. We propose that combined optical and nuclear imaging can detect tumor fragments less than 1 mm3 in vivo during removal of head and neck cancers. In fact, nuclear PET imaging alone may be highly successful - The current standard of care for evaluation and surveillance of regional and metastatic disease in head and neck squamous cell carcinoma (HNSCC) is FDG-PET/CT scan, which is highly sensitive but not specific. To address this, we show that a head and neck cancer, tumor-specific PET radiopharmaceutical can improve diagnostic specificity in this patient population. Citation Format: Eben L. Rosenthal, Marisa L. Hom, Goulan Lu. Fluorescence guided surgery: Rapidly evolving applications [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr IA12.